Localization of terminal complement components in damaged tissue implicates the membrane attack complex (MAC) in the pathogenesis of such inflammatory rheumatic disorders as synovitis and vasculitis in rheumatoid arthritis, lupus glomerulonephritis, and dermatomyositis. Alterations in host cells's defenses against autologous complement membrane attack are therefore likely to play a role in the pathogenesis of these diseases. The ~20-kDa complement inhibitory protein CD59, expressed on all blood cells and endothelial cells, interferes with the association of C9 with C8 in the MAC. The unusual structure that attaches CD59 protein to membranes, termed a glycosylinositol phospholipid (GIPL) anchor, can be cleaved enzymatically in situ to release functionally intact CD59 into the fluid phase. Soluble forms of CD59 have been identified in plasma, urine, and other fluids, but, at present, it is unknown whether soluble CD59 is derived by enzymatic cleavage of the anchor of membrane-bound CD59 or by some other mechanism, such as secretion from cells. The proposed studies are designed to identify mechanisms by which membrane-bound or soluble CD59's cyto- protective role is disrupted in inflammatory, rheumatic diseases whose pathogenesis involves deposition of terminal complement molecules. Specific Aims are: 1) To determine whether soluble CD59 protein in vivo bears structural remnants of the GIPL-anchor or membrane-bound CD59 protein. These studies will determine whether the GIPL anchor participates in a "quick-release" mechanism for rapidly introducing a complement inhibitor into the fluid phase. 2) to determine whether complement-mediated synovial cell damage is accompanied by (a) increased synovial-fluid concentration of soluble CD59, or (b) altered synovial endothelial tissue expression of CD59 in rheumatoid arthritis and other types of inflammatory arthritis. These studies will clarify mechanisms by which the synovium might evade MAC-mediated inflammatory injury in osteoarthritis but not rheumatoid arthritis or inflammatory arthritis. 3) To examine CD59's role in modulating endothelial procoagulant responses induced by the complement membrane attack complex. These studies will probe cellular mechanisms through which CD59 modulates MAC- mediated, procoagulant endothelial responses that connect vascular inflammation with rheumatic diseases. 4) To determine whether cell- specific variations in GIPL-anchor structure affect CD59's C9-inhibitory function. These studies will test a complementary hypothesis to that underlying Aim #1, that anchor structure is a key determinant of protein function. The proposed studies will shed light on the biologic function of the GIPL anchor structure. Knowledge of abnormalities in soluble and membrane CD59 that may exist in these diseases will improve our understanding of mechanisms of pathogenesis of MAC-mediated inflammatory diseases and guide design of new therapies.